Cancer is a devastating disease afflicting all communities worldwide. It has been estimated that 1 out of 2 men and 1 out 3 women will develop some form cancer within their lifetime.
Interestingly, it has been recently established that, regardless of the phenotypic variability between different cancer types, perturbation of limited number of genetic elements is sufficient to induce cellular transformation in many different human cell types (reviewed in (Zhao et al., 2004)). Experimentally, it was demonstrated that activation of Ras and telomerase (TERT), along with inactivation of the tumor suppressor proteins p53 and Retinoblastoma protein (Rb) can immortalize a variety of human cell types, which can subsequently transform to a tumorigenic state in response to inhibition of protein phosphatase 2A (PP2A). Therefore, these common genetic elements could be considered as master regulators of cancer development (Zhao et al., 2004).
PP2A is a widely conserved protein serine/threonine phosphatase (PSP) that functions as a trimeric protein complex consisting of a catalytic subunit (PP2Ac or C), a scaffold subunit (PR65 or A), and one of the alternative regulatory B subunits. As described above, recent experimental evidence has firmly established that inhibition of PP2A activity is a prerequisite for human cell transformation (reviewed in (Westermarck and Hahn, 2008)). Nevertheless, very little is known about mechanisms regulating PP2A complex composition and/or activity in vivo. Identification of PP2A inhibiting mechanisms might provide opportunities for development of novel class of cancer therapeutics re-activating PP2A tumor suppressor activity. This idea would be similar to cancer therapy approaches aiming at re-activation of tumor suppressor activity of p53 by small-molecules such as Nutlin-3 (Vassilev et al., 2004).
In 2007 a novel PP2A inhibitor protein designated Cancerous inhibitor of PP2A (CIP2A) was identified (Junttila et al., 2007). CIP2A interacts with PP2A and with one of the most important oncogenic transcription factors MYC. Moreover, siRNA-mediated depletion of CIP2A markedly increased PP2A activity in the MYC-PP2A complex and resulted in MYC serine 62 dephosphorylation and MYC protein degradation. It has also been demonstrated that CIP2A is required for the malignant cellular growth and for in vivo tumor formation (Junttila et al., 2007; Khanna et al., 2009; Westermarck and Hahn, 2008). Moreover, recent work has demonstrated overexpression of CIP2A in several common human malignancies and validated its role as a clinically relevant human oncoprotein (Khanna et al., 2009; Westermarck and Hahn, 2008). Thus, these results demonstrate that CIP2A is a novel human oncoprotein that inhibits PP2A in human malignancies.
Cell killing and/or apoptosis are the preferable endpoints for cancer therapy regimens. On the other hand, either intrinsic or acquired resistance is the major problem related to currently used chemotherapies. Thus, although at least some of the mechanisms underlying malignancy have been revealed, there exists a need in the art for the development of medicaments for hyperproliferative diseases and especially cancer. Activation of tumor suppressor protein p53 mediates apoptosis induction of cells in response to variety of the chemotherapeutics in clinical use. (Chari et al., 2009). However, as p53 function is impaired in approximately 50-70% of human cancers this is an important cause of chemotherapy resistance. (Chari et al., 2009). p53 is inactivated in cancer in most cases either by genetic mutations or by overexpression of negative regulators of p53 such as MDM2 or viral proteins such as human papillomavirus (HPV) 16 E6 protein. Thus, approaches that sensitizes those cancer cells that harbour functionally impaired p53 to chemotherapy are clearly needed in order to overcome the drug resistance (Chari et al., 2009).